ABSTRACT Combined nutrient- and oxygen-deprivation, as is experienced under ischemia, is an extreme stress for human cells and a fundamental hurdle, which most tumors have to overcome in their development. Various genetic changes, which enable cancer survival under these conditions, differently perturb many traits of the affected cells, including the likelihood of acquiring additional alterations, surviving outside of the designated niche and resisting therapy. A better understanding of these events would yield insights into resensitizing cancers to stress, and will provide prognostic markers for optimal disease management. We conducted a genome-wide shRNA screen for the genes whose inhibition protects epithelial cells in ischemia-like conditions. We validated ten candidates using individual testing, including confirming the role for one of them in acute renal ischemia in vivo. Some candidates also affect the response to genotoxic stress. The status of these genes is often altered in cancers and, in some cases, potently predicts clinical outcomes. Over a hundred candidates from our preliminary screen are still awaiting confirmation. We will test their role in ischemia tolerance and in cisplatin resistance using en masse validation procedures. Those involved in both processes will be investigated for the role in responsiveness to common anti-cancer drugs. The outcome will be a list of new regulators of cell stress response, and a set of predictions of how the status of these genes affects the management of the disease. Future work will explore these predictions, along with the underlying molecular mechanisms and the prospects of therapeutic targeting of the respective pathways.